The overall goal of this proposal is to utilize a rhesus monkey model to determine if exercise will protect against neurotoxic damage to nigrostriatal dopaminergic neurons in a primate species, and thereby serve to protect against Parkinson's disease (PD), or as a therapy in the early stages of the disease. Studies in rodents have shown that several forms of exercise (forced use by casting a forelimb, or wheel-running) can lead to plastic changes in the brain, including neuroprotection. Moreover, in rodents exercise can prevent or significantly mitigate the destruction of DA neurons by neurotoxins, protecting from the development of PD symptoms. Although the notion that exercise may protect against damage to dopaminergic neurons holds promise as part of a clinical strategy to protect against the development of PD, or as a therapy in the early stages of the disease, we currently do not have enough information to translate the findings in rodents into well founded recommendations for clinical application. A number of questions remain unanswered at this time, including whether exercise can have neuroprotective effects in primates. We have however, shown that exercise in the monkey leads to an increase in vascular volume in the motor cortex, an increase in neurogenesis in the hippocampus, and an increase in gliogenesis in the hippocampus and motor cortex. We are submitting this R21 application to (1) examine primate brain tissue that we have already collected from monkeys that were participating in a regular exercise regimen to determine if tissue changes indicative of neuroprotection have occurred in the nigrostriatal pathway, and (2) determine if there is any neuroprotective effect of exercise in preventing oxidative damage to the nigrostriatal pathway (caused by . MPTP administration) in nonhuman primates. Evidence for neuroprotective effects of exercise on the nigrostriatal pathway in primates would provide the necessary evidence to justify a larger grant application to address questions regarding the optimal type of exercise, the duration of exercise needed, and the mechanisms by which exercise may be useful as a preventative strategy or early treatment strategy for PD. [unreadable] [unreadable] [unreadable]